Fatty acids (FA) within triglycerides are the major source of energy storage in complex organisms and animals. Besides being an essential component of energy metabolism, FAs are involved in both intracellular and extracellular (autocrine and paracrine) and whole animal (endocrine) signaling processes. It is increasingly becoming evident that disturbances in FA metabolism are strongly associated with the pathogenesis of a large number of chronic conditions including the metabolic syndrome, inflammatory diseases and some cancers (Prentki et al., 2008, Endocrine Review, 29(6), 647-676). Among FAs, the short chain fatty acids (SCFA, carbon length C2-C6) are mainly produced during anaerobic bacterial fermentation of fibers in the gut (Sellin et al., 1999, News. Physiol. Sci, 14, 58-64). It has been found that short chain fatty acids (SCFA) bind to GPR43 (also known as FFAR2) (Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28, 25481-25489; Brown et al., 2003, The Journal of Biological Chemistry, 278, 13, 11312-11319). GPR43 expression has been shown in immune cells at least but not limited to polymorphonuclear leukocytes (PMN), purified neutrophils, peripheral blood mononuclear cells (PBMC), purified monocytes, eosinophils, and B lymphocytes ((Le Pouls et al., 2003, The Journal of Biological Chemistry, 278, 28, 25481-25489; Brown et al., 2003, The Journal of Biological Chemistry, 278, 13, 11312-11319; Stoddart et al., 2008, Pharmacological Reviews, 60, 405-417); and also in other tissues that may play a role in the propagation of the inflammatory response (e.g. intestinal cells or endothelial cells, Dass et al., 2007, Neurogastroenterl. Motil., 19:66-74; Karaki et al., 2006, Cell Tissue Res., 324/353-360). Recently, short chain fatty acids (SCFAs) have been shown to play a central role in the development of inflammatory conditions such as colitis, arthritis and asthma in a GPR43-dependent manner (K. M. Maslowski et al., 2009, Nature, 461, 1282-1287; C. Sina et al., 2009, The Journal of Immunology, 183:7514-7522). GPR43 knock-out (KO) mice were protected against chronic dextran sodium sulfate (DSS)-induced colitis. In a chronic DSS model, GPR43 KO mice presented less severe colon inflammation than wild-type (WT) mice, with a reduction of infiltrated polymorphonuclear leukocytes (PMN). The activity of granulocyte-specific MPO (myeloperoxidase) was reduced in GPR43 KO colon compared to WT colon, as well as TNFα levels. SCFA have been shown to induce neutrophil migration both in vitro with isolated neutrophilic granulocytes and in vivo in an inflamed air pouch model. GPR43 KO isolated neutrophilic granulocytes lost the ability to migrate in response to SCFAs, suggesting key function of GPR43 is neutrophilic granulocytes (C. Sina et al., 2009, The Journal of Immunology, 183:7514-7522).
GPR43 KO mice were protected from high fat diet (HFD)-induced obesity and dyslipidemia (Bjursell et al., 2011, Am. J. Physiol. Endocrinol. Metab. 300:(11) E211-E220). GPR43 KO mice presented higher lean body mass and lower body fat mass than compared to WT mice. Plasma adiponectin levels were increased in GPR43 KO mice as compared to littermate controls. The liver of GPR43 KO mice showed reduced triglyceride content. Moreover, insulin sensitivity was improved by GPR43 gene ablation as GPR43 KO mice displayed lower insulin levels, but normal glucose levels, in the oral glucose tolerance test. In addition the reduced macrophage content in GPR43 KO adipose tissue compared to WT mice indicated a protection from HFD induced adipose inflammation. Finally, GPR43 KO mice were also found to be protected from HFD-induced hypercholesterolemia. The improved metabolic profile observed under HFD in GPR43-deficient mice is likely explained, at least in part, by an increase in energy expenditure.
GPR43 was recently implicated in carcinogenesis (Hatanaka et al., 2010, Cancer Sci., 101:54-59). GPR43 expression (both mRNA and protein) was increased in digestive tract cancer tissues compared to normal digestive tract tissues. 3T3 cells infected with recombinant retrovirus encoding GPR43 and treated with acetate shown a pronounced increase in proliferation. 3T3 cells infected with recombinant retrovirus encoding GPR43 were tested for tumorigenicity in athymic nude mice. Tumor formation was apparent with 4 tumors developed for 4 injections, similar to 3T3 cells infected with recombinant retrovirus encoding v-Ras (8/8 tumor/injection), but in opposition to 3T3 cells infected with empty virus (0/8 tumor/injection).
Therefore, the present invention provides novel compounds, processes for their preparation and their use in the preparation of a medicament for the treatment of inflammatory conditions, infectious diseases, autoimmune diseases, diseases involving impairment of immune cell functions, cardiometabolic diseases, and/or proliferative diseases.